Eliminating HIV persistence is an obligated step to curing HIV/AIDS disease. Indeed, life-long highly active antiretroviral therapy is required since current antiviral drugs fail to eliminate the virus from HIV-infected patients. Despite intensive research there are no effective strategies to eliminate latent, transcriptionally silent HIV proviruses from HIV infected patients with well-controlled HIV infection. Emerging evidence suggest that CD4+ T memory stem cells (TSCM), the least differentiated of all CD4+ T cell memory populations, support HIV infection. There remains, however, a fundamental gap in our knowledge regarding the mechanisms and the extent of the impact of CD4+ T cells with stem like properties (TSMC) on establishment of HIV latency and persistence. Our preliminary data suggests that TSCM are fundamentally different from other CD4+ T memory cells. Since stem cells can renew and generate progeny cells for prolonged periods, we hypothesize that infected TSCM persist, maintain and seed CD4 T cells carrying latent proviruses. We will use mass-cytometry, 3D-FISH, proteomics and genomics to probe for the molecular mechanisms of latency establishment and maintenance specific for primary human CD4 T stem cells. We will define correlates of abortive, silent and productive infections in CD4+ TSCM, define the cellular programs specific for HIV persistence in CD4+ TSCM and probe for the CD4+ TSCM reservoir in HIV positive patients with spontaneous or HAART-assisted control of HIV infection. We will test to what extent a small number of integrations can seed the reservoir carrying the same latent provirus over multiple cell generations. Understanding the molecular mechanisms underlying latency establishment and maintenance in CD4+ TSCM is essential to develop targeted interventions aimed at shrinking and purging HIV persistence in CD4+ TSCM.